Hydrophenanthrene carboxylic acid intermediates



Patented Jan. 25, 1949 ()FFICE IiYDROPI-IENANTHRENE CARBOXYLIC AID 4 INTEBMEDIATES j Karl Miescher, Riehen, and Georg Anner, Basel, Switzerland, assignors to Ciha Pharmaceutical Products, 1110., Summit, N. .l.

i No Drawing. Application May 13, 1946, Serial No.

669,462. In Switzerland November 30, 1944 3 Claims.

This application is a continuation-in-part of our copending application, Serial No. 622,092, filed October 12, 1945.

This invention relates Zto hydrophenanthrene carboxylic acids, their derivatives and to the preparation thereof. a ,f

In copending application, Serial No. 542,812, filed June 29, 1944, there is described a process for the manufacture of hydroxy-hydrophenanthrene carboxylic acids or derivatives thereof consisting in causing l-ketohydrophenanthrenes which contain in the 2 position, in addition to a hydrocarbon radical, a functionally converted carboxyl group and in the 7-position a free phenolic hydroxyl group or a substituent convertible into such a group, to react with an organo-metallic compound for the purpose of introducing a hydrocarbon radical into the 1-position, then directly or indirectly eliminating the newly formed tertiary hydroxyl group, and, if desired, converting the functionally converted'carboxyl group in 2-position into a free carboxyl group and/or the substituent in 7-positiorr into a free hydroxyl group, and hydrogenating non-aromatic multiple carbon linkages at any desired stage after the reaction with the organogmetallic compound.

This process is relatively circumstantial, especially when considering the fact that the manufacture of the necessary. starting materials is cumbersome and requires many steps. Thus, a seven-step synthesis is necessary only for obtaining the parent materials, starting from l-[fihalogen-ethyl]-6-methoxvnaphthalene [cf W. E. Bachman, J ourn. Am. soc vol. 61, page974 (1939) and vol. 62, page 824 (1940)]. According to the present invention the same final products, as well as corresponding compounds which in the 7+position do not carry one of the named substituents, are obtained in an essentially shorter way? by treating napthalene derivatives containing inf 2-position a hydrogen atom capable of condensation, and in l-position stituted hydrocarbon radical, with agents which effect ring closure either directly or indirectly, if necessary eliminating a produced tertiary hydroxyl group directly or by the 'way of intermediate products, and, if desired, causing hydrogenating agents and/or agents to react with the resulting product which convert any substituent which maybe present in 7-position and which is convertible into a phenolic hydroxyl or thefunctionally converted carboxyl group into a free hydroxyl group or a carboxyl group, respectively.

The present process is relatively simple and has moreover the advantage that the necessary starting materials are easily producible. Thus they can be obtained, for example, by starting from 1- [p-halogen-alkyll-naphthalenes, by I reaction with aliphatic ,c-keto-carborrylic" acids whose carboxyl group is functionally converted for instance into an esterfied carboxyl or nitrile group and which contain in a-position a'hydrocarbon radical and a hydrogen atom. There may as well be reacted fi-keto-carboxylic acid derivatives which contain two hydrogen atoms in u-position, and the resulting products may be treated with hydrocarbon halides. Of the aforesaid ketones, metal salts such as the alkali or. magnesium compounds for instance, are advantageously used. The condensation is preferably carried out in solvents such as benzene, toluene or-xylene, either alone or mixed with higher alcohols, for example, amylene hydrate or tertiary butyl alcohol. Starting materials are preferably used which contain in G-position a group which is convertible into a phenolic hydroxyl. This substituent standing in fi-position may be, for examplea hydroxyl group etherified by methanol, ethanol, phenols, benzylalcohols or thelike, or a hydroxyl group esterified by organic or inorganic acids, a nitroor amino group or a halogen atom. The starting materials may be partially hydrogenated in the nucleus and contain further substituents in the nucleus itself as well as in the side chain.

For the purpose of comparisonthere is shown below the known and the new way for synthesizing the '7 methoxy 1 ethyl 1 hydroxy-2- methyl- 2 -carbome.thoxy-l:2;3:4 tetrahydrophenanthrene and the Z-meth0xy-l-ethylidene- 2-methyl-2-carbomethoxy-1 2 :3 :4 tetrahydrophenanthrene respectively, starting from 1-[ebromoethyl] G-methoxy- 1 -naphthalene:

According to the present process these startin materials are treated with agents bringing about ring closure either directly or indirectly.

In-the case of direct ring closure, depending on the condensing agents and/or the conditions of reaction, water is eliminated or tertiary carbinol compounds are-formed atfirst. I The newly formed tertiary hydroxyl group may be removed directly or by way of intermediate products.- This may happen, for example, with formation of a carbon double bond. To this end water is eliminated directly, or the hydroxyl group is first replaced by a halogen, or another ester or ether radical. Subsequently a hydroxyl changed in this way may be eliminated by thermic decomposition or by treatment with agents which eliminate acid or alcohol. The removal of the tertiary'hydroxyl group or of the halogen atom can also be undertaken by reduction, e. g. with the help of hydrogen in the presence of a precious metal catalyst, or

also with hydriodic acid in the presence Of glacial acetic acid. The double bonds formed by direct ring closure may be saturated with hydrogen.

If ring closure has to take place indirectly, the keto group is at first converted into a secondary or tertiary carbinol group, either directly with the aid of reducing agents or by reaction with organo-metallic compounds, such as alkyl, alkenyl or alkinyl magnesium halides, alkinyl alkali compounds and the like, and water is then eliminated. Here, too, the ring closure can be effected directly or by way of intermediate products.

As condensing agents there can be used, inter alia, more or less concentrated sulfuric acid, phosphoric acid, phosphorus oxy chloride, phosphorus pentoxide or mixtures thereof as such or in the presence of suitable solvents, such as glacial acetic acid or benzene. Simultaneously with the ring closure a saponification of groups capable of being hydrolyzed may take place. This is the case, for example, if the condensing agent used is aqueous and if, for example, secondarily bound carbalkoxy groups are present in the starting material which groups, as is known, can often be better saponified to free carboxylic groups than ter'tiarily bound carbalkoxy groups.

Any groups convertible into phenolic hydroxyl groups still present as well as functionally converted carboxylic acid groups, for example, nitrileor carbalkoxy groups, are converted, if necessary, into free hydroxyl or carboxyl groups. For this there are used hydrolyzing agents, particularly in the presence of. esters and ethers, further aluminum halides, pyridine salts and the like. In case that benzyl groups or the like are split off, also reducing agents may be used. a

The hydrophenanthrene carboxylic acids or their derivatives thus obtained may also be converted into their carboxylic acid esters and/or hydroxy hydrophenanthrene compounds into their phenol esters or phenol ethers. Furthermore, free carboxylic acids may be converted into carboxylic acid salts.

The new compounds find application in therapeutics or as intermediate products for the preparation of therapeutic substances.

The following examples illustrate the invention without in any way limiting its scope, the parts being by Weight:

Example ,1 v 5. parts of -(6'-methoxy-naphthyl-1')-3- methyl-3-carbomethoxy-pentane-2-one 1 of .the formula 1 CH3 1:, M f mcoocm are treated for several hours with 25 parts of ortho-phosphoric acid, while stirring. After performed cyclisation the reaction mixture is poured into much water and the precipitated oily product is taken'up mother. The ethereal solution which has been Washed until neutral and dried is evaporated andto the residue is added a little methyl alcohol. The '7-methoxy-1-methylene-2-methyl- 2 i-carbomethoxy 1:2:324 tetrahydrophenanthrene of the formula CH3 ooo0H3 crystallizes out after some time. When recrystallized from isopropylether it melts at 98-100 C.

For. the "purpose of saponifying the carboxyl' group 1 part of this compound is heated for a short time in'. the oil bath to C. in a mixture of .3 partsof potassium hydroxide, 0.5 part of water and 0.5 part of methyl alcohol. The reaction mixture is then taken up in water, the solution is acidified and the 7-methoxy-l-methylene-2- methyl-Z-carboxy 1:2:3z4 tetrahydrophenanthrene is thus obtained. After recrystallization from acetone it melts at 189 C.

By hydrogenation'in an aqueous alcoholic alkalinesblution in the presence of a nickel catalyst it can be converted into the 7-methoxy-lz2- dimethyl-2-carboxy-1 2 3 4 tetrahydrophenanth'r'enfof melting point 228 C. This acid can be converted into the 7-hydroxy-1:2-dlmethyl-2- carboxy 1:2:3z4 tetrahydrophenanthrene by boiling with a mixture of glacial acetic acid and hydrochloric acid. When recrystallized from dilute alcohol it melts at 249-250 C.

Instead of bringing about ring closure directly, one may at first reduce the starting material, for example, with catalytically activated or nascent hydrogen or an aluminum alcoholate or -phenolate in the presence of isopropyl alcohol, to the 5 (6'-methoxy-naphthyl-1') -3-methyl-3-carbomethoxy-pentane-Z-ol, and then treat this compound with agents bringing about ring closure. The reduction of the keto group into a carbinol group can also be eiiected by reaction with a suitable organo-metallic compound, such as isopropyl magnesium bromide.

The starting material can be obtained, for example, in the following manner: I a

(a) A mixture of 15 parts of potassium in 30 parts of methyl alcohol and 25 parts of benzene is mixed witli8.25 parts of acetoacetic'acid methylester, and heated until the solution is clear. 79.5 I parts i of 1-' (c-bromo-ethyl) fi-methoxy naphthalene are added to the cooled solution and heated for several hours under reflux. After cooling the mixture is acidified with glacial acetic acid, the solvents are evaporated and the acetoacetic ester in excess is. removed in vacuo. The residue shows a positive color reactlon with ferric chloride. For the purposeof methylationit is dissolved in 300 parts of benzene, the solution is boiled for a short time with sodium methoxide obtained from '7 parts of sodium, and, after cooling, mil -parts oi-methyliodide are allowed to drop thereto. When the reaction is complete the1=reaction mixtureisheated' for a further 2 hoursunderQ reflux, then poured into dilute acetic acid and takenlup in ether. The. 5- (6-methoxy-naphthyl- 1) -3 emethyI-S-carbomethoxymentane 2' one thus obtained can be distilled at1192-195" C. under, -.11 mm.pressure'without being decomposed and does not show a' color reaction with. ferric.

chloride. V (b) 58.5 parts of potassium are pulverized un cooling partly precipitates. There follows mixing with 300 parts of l-(p-iodine-ethyl) -6-methoxynaphthalene in 600 parts of benzene. The mixture is boiled under nitrogen for 50 hours and worked up as above indicated. The '5-(6'-meth-' oxy-naphthyl-l') -3-carbethoxy-pentane-2-one is a thick oil of pale yellow color and boils under 0.2 mm. pressure at a temperature of 190-200 C.

9e. parts of the. aforesaid -(6f-methoxy-naph; thyl-ll-3-carbethoxy pentane- 2:- one in .200- parts of benzene. are. added to 11.7 parts of pulverized potassium and 500 parts of benzene. and the whole. is refluxed for about 1 hour. Aftercooling, 1-00parts of methyliodide. are added drop by drop- The whole is allowed to. standfor hours at room temperature and then again refluxed for minutes before the cooled mixture.

is. poured; into ice water. The aqueous solution; shows a slightly alkaline reaction. The-solvent is washed neutral, dried and evaporated. The? reaction product is purified by distillation in high vacuo. The 5 (6 methoxynaphthyly-l'l-E-a methyle3-carbethoxy-hexane-2 one so obtained boil'squnder 0.05 mm. pressure at a. temperature:v of lilo-190 C. and shows a negative ferri-chloride reaction.v

Example 2 5 I parts of 6'-(6 -methoxy-naphthyl-l'i) .-4:. methyl-d-carbomethoxy-hexane 3 one of the formula. V

. CH3 W 0 0 o 0113 c o CHzCHl! recrystallization from dilute methyl alcohol.

81-: etluer.v filhe ethereal solution is washed until neutral,.-dried.and evaporated; The residue is crystallized from isopropyl ether, whereby the -7- methoxy hethylidene-Z-methylz 2 carbometh ox-y -l:213.:e tetrahydrophenanthrene of melting -981l6- C. isobtained', q r l part'of this compound is dissolvedin 10 parts of glacialacetic acid a nd hydrogenated with the aid ef;0.l'part oi palladium animal charcoal, the quantity of; hydrogen, calculated for 1 mol being takeni-na The whole is filtered to remove the catalyst, the filtrate is evaporated and 7-methoxy-l:ethyl-2emethyl-2carbomethoxy 122:3:4-

tetrahydrophenanthrene is thus obtained. By-

heating to. 200 C. with an aqueous solution of potassium hydroxidethis can besaponified to the '7 methoxy-l-ethyl-2-methyl-2 carboxy-1 3:15:4- tetrahydrcphenanthrene which melts at 228- 230 C. after recrystallization from acetone. The methoxy-group is Split by heating to l70-180 :C. with; pyridine hydrochloride. The resulting "7- hydroxy 1" ethyl-2-methyl-2-carboxy-1.:2:3z4- tetrahydrophenanthrene. melts, at 204 C. after It canal-so be: obtained by a single saponification. at;'i-methoxy-l-ethylzemethyl 2 carbometlroxy-l :2 :3-:.vtetrahydrophenanthrene on heating wttlra; methyl alcoholic solution of caustic potash.

in .aiclosedtube; r

Analogous final. products are also obtained-by starting: from other (i-(fi alkoxy naphthyl-l')- 4 alkyl l-carbarhoxy hexane 3 ones or from other .4.c.arboxylic. acid derivatives, such aslor example, from nitriles. instead of derivatives of the acetoacetic acid ester or homologues' thereof,

' there-may also be used as starting materials, for

example, derivatives of the B-ketQ-adi'pinic acid ester or naphthalenecompounds partially hydrogenated the ring carrying the side chain and containing in Z-psiticn at least one hydrogen atom capable of condensation. Such starting materi-al's' can also be-usedwhose naphthalenenucleus or ethylene bridge is further substituted by a-l-kyl', halogen andthe'like.

Fonthering condensation there-can be'usecl, instead of a mixture of phosphoricacid and sulf uric acid, for: example, also phosphoric acid, sulfuric" acid; phosphorus pentoxide or phosphorus"oXy -chloride as such or in the presence of a suitable solvent, such as glacial acetic'acid.

or'l'lenzene.

The hydroxy-carboxylic acids or their esters thus' obtained'canbe convertedflinto the correspondingiphenolesters orphen-ol ethers, for ex.- ample,int o the propionates, butyrateapalmitates or benzoatesor into the methoxyor ethoxy compounds. Al'soiwater-soluble salts, for example, alkali, alkaline earth or ammonium salts can be prepared from the free hydroxy carboxylic' acids.

on from the hydroxy-carboxylic acids esterified' orethei'ified' at the phenol group.

The starting material mentioned "at the be-' ginning of this example may beobtained in the followingimanner, for example:

* 21 6'parts of 'a-propionyl-propionic acidmethyl ester are slowly added to: 50 parts oi pulverized 'potassium under I000 parts. of. xylene. "Reaction sets; insimmediately andthe: crystalline potassium salt is formed. The last traces of potassium are caused to react by boiling for a short time. The

whole" is then allowed to cool and a solution of 265 iparts: of 1-. (B bromoethyl) -6-metho'xy-naph th'ale'ne in 7500 parts ofxylene is added; 1111- mediately following this, themixture is refluxed J for 64 hours under nitrogen, then cooled and poured intoice-cold acetic acid. The xylene solution is washed with sodium-bicarbonate solution and water and the solvent is evaporated. Through distillation in high vacuum the pure 6- (6-methoxy-naphthyl-1.'),-4-methy1 4 carbomethoxy-hexane-3-oneis obtained. Its boiling point at 0.05 mm. pressure is at 185-195 C. and it melts at 57.559.5 C. The corresponding ethyl ester is prepared as follows:

195.5 parts of potassium are added to a mixture of 600 parts of amylenehydrate and 4000 parts of xylene. By gradually heating to 100 C. while stirring a clear solution is obtained after about 3-4 hours. Upon cooling to 30-40 C. the potassium salt partly precipitates. To this mixture 869 parts of a-propionyl-propionic acid ethylester are quickly added, the temperature rising to 60-70 C. 1192.5 parts of melted 1- (fl-bromo-ethyl) 6- methoxy-naphthalene are then poured into the mixture, followed by flushing with 1000 partsof xylene and the wholeis then heated immediately. to ion-110 C. under nitrogen ,for 60 hours. After cooling, the mixture is poured on toice and water, mixed with a small excess of hydrochloric acid and washed with diluted caustic soda solution and water. The residue is then fractioned in high vacuo. The 6 (6 methoxy-naphthyl-l') -4-methyl-4- carbethoxy-hexane-3-one boils under 0.1-0.2 mm. pressure at 195-210 C. and it can be re crystallized from petroleum ether. Melting point, 42-44" C.

used instead of potassium.

Ewample 3 66 parts of 6-(6'-methoxy-naphthyl-1')-4- methyl 4 carbomethoxy hexane 3 one are mixed with 1500 parts of ice-cold sulfuric acid of 80 percent strength andshaken at C. until complete solution has occurred. The reaction starts immediately with formation of a redbrown coloration. After some hours the whole is pouredonto ice and the precipitated reaction product taken up in ether. After evaporation, the ether solution which has been washed until neutral, leaves behind a brownish oil which crystallizes (21 parts) when mixed with isopropylether. I By recrystallizing it from alcohol there is obtained the pure 7-methoxy-l-hydroxy- 1 ethyl 2 methyl 2 carbomethoxy-1t2z3z4- tetrahydrophenanthrene of melting point 128- 129.5 C. and of the formula From the mother liquors a further crystal fraction (8.4 parts) can be isolated in the cold which when recrystallized repeatedly from alcohol melts at 152-153. 5 C. and represents the eplmeric 7 methoxy 1 hydroxy-l-ethyl-Z- methyl-Z-carbomethoxy --1:2:3:4 tetrahydrophenanthrene. From the last mother liquors the two isomeric 7-methoxy-L-ethylidene-Z-methyl- 2-carbomethoxy 1:2:3:4'=- tetrahydrophenan- 10 threnes of melting points 118-119 C. or 134-137 C. can finally be obtained after evaporating, recrystallizing from methanol and chromatographing on aluminum oxide.

25 parts of a mixture of the two epimeric 'lmethoxy l-hydroxy-1-ethyl-2-methyl-2-carbomethoxy-lz2z3z4 tetrahydrophenanthrenes are heated on the water-bath for 1 hours with 0.5 part of iodine and 250 parts of chloroform. The reaction mixture is poured into water, the iodine is removed with thiosulfate solution, the solvent is dried and evaporated. The two isomeric"?- methoxy-1-ethylidene-2-methyl-2 carbomethoxy-l:2:3:4-tetrahydrophenanthrenes of melting points 118-119 C. or 134-137 C. can be separated from the residue. The two unsaturated esters are thus formed in proportion 1:1. If the elimination of water is brought about with formic acid alone instead of with iodine in chloroform, there are obtained, after working up, of the isomer of melting point 118-119 C. and of the isomer of melting point 134-137 C. The latter can be converted into the former in about the following manner: 2.5 parts of the unsaturated ester of melting point 134-437 C. in 30 parts of chloroform are heated for 2 hours on the waterbath under reflux with 0.05 part of iodine. The product is then worked up as usual. Equal parts of the unsaturated esters of melting points 134- 137 C. and 118-119 C. are obtained.

27 parts of a mixture of the two unsaturated esters of melting point 118-119 C. and 134-137 C., respectively, are introduced at C. into a mixture of 53 parts of potassium hydroxide, 15 parts of water and 15 parts of alcohol. The temperature is allowed to rise to C. The potassium salts of the two isomeric unsaturated acids are precipitated in solid form in practically quantitative yield. For the purpose of removing small quantities of starting material the aqueous solution of the potassium salts is shaken with ether and acidified. The two isomeric '7- methoxy-1-ethylidene-2-methyl 2 carboxy- 1:2:3;4-tetrahydrophenanthrenes can be purified byfractional crystallization from alcohol. In the pure state they have a melting point of -186 C. and 213-215 C., respectively. Both acids melt with decomposition.

15 parts of a mixture of these two unsaturated acids are dissolved in 700 parts of waterand 20 parts of sodium hydroxide and hydrogenated with 20 parts of a nickel catalyst at 50 C. under atmospheric pressure. After the calculated quantity of hydrogen has been absorbed the hydrogenation comes to an end. The alkaline solution is then acidified and the 7-methoxy-1-ethyl- 2-methy1-2-carboxy 112:3:4 tetrahydrophenanthrenes obtained in the form of grains are suction-filtered and recrystallized from acetone. 12.? parts of the physiologically active acid of melting point 228-230 C. and 1.3 parts of'the isomeric acid of melting point 204-206 C. are obtained. On using not so large an excess of alkali hydroxide during the hydrogenation the yield of the physiologically active acid is lowered and more of the isomeric acid is obtained. When the hydrogenation is performed in neutral or acid solution practically only the isomeric acid is produced.

8.6 parts or the saturated methoxy acid of melting point 223-230 C. in a mixture of 32 parts of potassium hydroxide and 80 parts of methanol are heated for 7 hours in an autoclave to 210 C.

11 of decolorizing theethereal solution, the Whole is shaken with little saturated sodium bicarbonate solution. After evaporating the solventthere are obtained 8 parts of '7-hydroXy-1-ethyl-2-methyl- 2 carboxy 122:3:4 tetrahydrophenanthrene melting at 204 C. after recrystallization from acetic ester. 7

The same final product is also obtained by removing the hydroxyl group of thefl methoxy-h hydroXyJ-ethyl-Z methyl 2 carbomethoxy- 1:2:3: l-tetrahydrophenanthrene at grst directly by reduction, for example with hydriodic acid.

This hydroxyl group, however, can also be converted, e. g. replaced by halogen, whereupon halogen hydride can be eliminated from the compound thus obtained, andrthe resulting double bond can subsequently be hydrogenated or the halogen can be removed from the halogen ooh pound by reduction. For the purpose of saponifying themethoxy and/ or carbomethoxy group the product'is then treated with hydrolyzing agents, if necessary.

Example 4 10.9 parts of G-(naphthyl-l)-4-methyl--4-carbomethoXy-hexane-3-one are shaken at C. for 16 hours with 450 parts of sulfuric acid of 90 percent strength. The dark blue colored solution is poured on to ice and taken up in ether. 'After Washing, drying and evaporating the solvent the reaction product is obtained in the form of an oil. In a manneranalogous to Example 3, the lethylidene- Z-methyl-Z-carboxy 1:213: 1 tetrahydrophenanthrene is isolated therefrom by sa precipitated methylalcohol recrystallized. The 1- ethyl-2-methyl-2-carboxy 122:3: l tetrahydrophenanthrene so obtained melts at 2'16- 21'8 C.

The above mentioned starting mat-eria1can be obtained in the following manner:

47 parts of are refluxed for 60 hours with the potassium salt from 7.8 parts of potassium and 28.8 parts of apropionylpropionic acid methyl ester in 406 parts of1xylene. After working up asset iorthin Example 2, the pure e-(naphthyl-l')e niethyllcarbomethoxy-hexane-S-one, is obtained which boils at loo-165 C; under 0.05 mm. pressure,

7 Example 7.7 parts of 5-(6'-inethoxy-naphthyl-l") -3- .methyl-'3-carbethoxy-pentane-Z-one in parts of benzene are run at 0 C. into a Grignard solution prepared from 3.3 parts of ethyl-bromide and 0.81 part of magnesium in 20 parts of ether. A change of color occurs immediately. The clear,

greenish colored solution is allowed to stand for 14 hours at room temperature and then boiled under reflux for 1 /2 hours. After cooling the mixture is decomposed with ice and ammonium 1- (,B-bromo-ethyl) -na hthalene 'aralkyl or aryl group.

cl'gloridef After evaporating; 'thewashed and dried ethereal solution laves'behind 8.1 parts o distilled in ahigh vacuo and is therefore worked up lwithour further purification. ..It represents the 6-(6.-methoXynaphthyl- 1)' 3 -hydroxy 3: i-dimethyl-4-cafbethoxy-hexane of the formule. i

A solutionofB parts of this-crude compound in 10 parts of; ether is introduced indropswithin 1 hours-at ;-'3 C., while stirring, into 30 parts of sulfuric acid of percent'strength. The dark red colored solution issubsequentlyallowed to stand for 3hours at 10 C. It. is rthen poured ontoice and the reaction produot is taken up in, ether. For the purpose of saponifying the esterified carboxyl group, the ether residue is heated with causticpotash solution for a short time to C., as indicatedin Example 3. The Z-methoxy -lethyl --1 :2- dimethyl -2- ca'rboxy- 1 2 3 i tetrahydrophenanthrene thus. obtained of the formula I melts, after recrystallisation from methanol; at -l38 C. without decomposition. It can be converted into the 7-hydroXy-1-ethyl' 1-12 '7 dimethyl-Zwarboxy tetrahydroph'enanthrene, for example; by heating with pyridinehydrochloride. As starting'materials there: can; also be used other 5 (6-alkoxy-naphthyl-1')-3-alky1-3 carbalkoxy pentane 2 -'ones or their side chain homologues, as wellas otherfagents capable of converting the group C;O in-the 'sidechain into thegroup wherein R' represents; for example, an alkyl,

In a manner analogous-to that described in the'foregoing examples, there can generally be roduced the compounds of the formula Certificate of Correction Patent No. 2,459,950. January 25, 1949.

KARL MIESGHER ET AL. It is hereby certified that errors appear in the above numbered patent requiring correction as follows:

In the grant, line 1, name of inventor, for Karl Meischer read Karl Miescher; in the printed specification, column 1, line 34, for Bachman read Bachmmm; line 40, for napthalene read naphthalene; column 2, line 19, for esterfied read estemfiecl; column 11, line 11, for grst read first; column 12, lines 10 to 17, for that portion of the formula reading CH] CH;

read Y on on and that the said Letters Patent should be read with these corrections therein that the same may conform to the record of the case 111 the Patent Oflice.

Signed and sealed this 14th day of June, A. D. 1949.

THOMAS F. MURPHY,

Assistant Oonmiaaiomr of Potato. 

